Pharmacokinetics and Pharmacodynamics of Mepolizumab, an Anti-Interleukin-5 Monoclonal Antibody

Abstract

Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05-10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93 mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64-75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 μg/mL.

Pharmacokinetics and pharmacodynamics of mepolizumab, an anti–interleukin 5 monoclonal antibody, in healthy Japanese male subjects

“…The mean t 1/2 values in the 75‐ and 750‐mg groups in this study were relatively similar (20 and 23 days, respectively) to the previous phase 1 study,3 but the mean t 1/2 (36 days) following administration of mepolizumab 250 mg was longer than in the previous phase 1 study (18.5 days). 3 The t 1/2 variability was higher at 250 mg than at 75 and 750 mg in this study. The reason for the longer t 1/2 in the 250‐mg group is not fully understood, although the greater variability in this cohort of 7 subjects is likely a contributing factor.…”

“…Mepolizumab has been reported to consistently and significantly reduce peripheral and tissue eosinophils in patients with asthma and in healthy volunteers 2, 3, 4…”

Mepolizumab treatment for asthma

“…At doses used in clinical studies it led to a greater than 85% reduction in peripheral blood eosinophils with an IC 50 of around 0.45 µg/mL [20].…”

“…Leckie et al [20] DBPC mild asthma (SABA only) 8 placebo, 8 2.5 mg/kg 8 10 mg/kg Single dose i.v. Allergen challenge (AgCh) 5 --10x decrease in blood eos (10 mg dose) no change in AHR before or after AgCh no change in late asthmatic response Buttner [21] DBPC mod asthma (on ICS) 8 placebo, 8 250 mg, 8 750 mg 3 doses i.v.…”

Accurately measuring and modeling Th2 and Th17 endotypes in severe asthma

“…Nitric oxide is produced by the action of iNOS encoded by the NOS2 gene, and eosinophils are mobilized by chemokines such as eotaxin-3 encoded by the CCL26 gene, both of which are inducible by IL-13 and highly correlated with the Th2 signature (18). The half life of blood eosinophils in humans is several days (19) and it is likely that serum periostin levels may fluctuate on a similar time scale (20), while serial bronchoscopy studies with anti-IL5 suggest that bronchial tissue, but not sputum eosinophils, may persist for weeks to months (21). Thus, FeNO and sputum eosinophils may reflect acute activity of type 2 cytokines in the airways whereas tissue eosinophils and blood biomarkers may reflect aggregate type 2 airway inflammation over longer time intervals.…”